1. Field of the Invention
The present invention relates to 2-carboxamide piperazine compounds, and methods of treatment and pharmaceutical compositions that utilize or comprise one or more such compounds. Compounds of the invention are useful for the treatment of mammalian infertility.
2. Background
Luteinizing Hormone (LH) and Follicle Stimulating Hormone (FSH) are produced by the anterior pituitary gland and are involved in mammalian reproductive processes. The glycoprotein family of pituitary hormones such as FSH, LH and the thyrotropic hormone (TSH) relatively large heterodimeric proteins that contain carbohydrate moieties. They have a common α-subunit and distinct β-subunits (1-4) providing receptor recognition and specificity.
LH is released from the anterior pituitary gland under the influence of gonadotropin releasing hormone and progesterins. In the female LH stimulates ovulation and is the major hormone involved in the regulation of progesterone secretion by the corpus luteum. In the male, LH stimulates Leydig cells to secrete androgens, particularly testosterone.
FSH is released from the anterior pituary under the influence of the gonadotrophin releasing hormone, and oestrogens and from the placenta during pregnancy. FSH acts on the ovaries stimulating maturation of follicles and regulates secretion of oestrogens. In the male, FSH is responsible for the integrity of the seminiferous tubules and acts on Sertoli cells to support gametogenesis.
The LH and FSH receptors belong to the superfamily of G-protein coupled receptors, which are complex transmembrane proteins characterized by seven hydrophobic helices. The LH and FSH receptors also share close sequence homology (approximately 40%). The receptors' extracellular domains bind to their respective hormones with high affinity and specificity. The intracellular portions of FSH and LH receptors are coupled to a Gs protein. Receptor activation upon the hormonal interaction with the extracellular domain results in a cascade of events that leads to specific biological effects.
LH and FSH have been used for the treatment of female infertility and spermatogenesis disorders. See U.S. Pat. Nos. 5,767,067; 5,639,639; and 5,017,557.
However, those therapies have some notable shortcomings. For instance, current FSH treatment is limited by lack of oral bioavailability, high costs and need of close medical personnel supervision throughout an administration protocol.
Certain non-peptidic FSH agonists also have been disclosed. See, for instance, U.S. Pat. Nos. 6,235,755; 6,423,723; WO 00/08015; and WO 02/09706.
Thus, it would be desirable to have new agents and methods to treat infertility in mammals.